Design, synthesis, and biological evaluation of 3-aryl-3-hydroxy-1-phenylpyrrolidine derivatives as novel androgen receptor antagonists.

Article Details

Citation

Yamamoto S, Kobayashi H, Kaku T, Aikawa K, Hara T, Yamaoka M, Kanzaki N, Hasuoka A, Baba A, Ito M

Design, synthesis, and biological evaluation of 3-aryl-3-hydroxy-1-phenylpyrrolidine derivatives as novel androgen receptor antagonists.

Bioorg Med Chem. 2013 Jan 1;21(1):70-83. doi: 10.1016/j.bmc.2012.11.001. Epub 2012 Nov 12.

PubMed ID
23199477 [ View in PubMed
]
Abstract

We designed and synthesized a series of 3-aryl-3-hydroxy-1-phenylpyrrolidine derivatives D and evaluated their potential as novel androgen receptor (AR) antagonists therapeutically effective against castration-resistant prostate cancer (CRPC). Introduction of a methyl group at the 2-position (R(2)) of the pyrrolidine ring increased the AR binding affinity. The (2S,3R) configuration of the pyrrolidine ring was favorable for the AR antagonistic activity. It was found that introduction of an amide substituent (R(1)) and a pyridin-3-yl group (Q) was effective for reducing the AR agonistic activity which appeared during the optimization of lead compound 6. Compound 54 showed potent antitumor effects against a CRPC model of LNCaP-hr cell line in a mouse xenograft, in which bicalutamide exhibited only partial suppression of tumor growth. Thus, the pyrrolidine derivatives such as 54 are novel AR antagonists, and their properties having efficacy against CRPC are distinct from those of a representative first-generation antagonist, bicalutamide.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
BicalutamideAndrogen receptorEC 50 (nM)>10000N/AN/ADetails
BicalutamideAndrogen receptorIC 50 (nM)330N/AN/ADetails
BicalutamideAndrogen receptorIC 50 (nM)54N/AN/ADetails
StanoloneAndrogen receptorIC 50 (nM)>10000N/AN/ADetails
StanoloneAndrogen receptorEC 50 (nM)6.2N/AN/ADetails
StanoloneAndrogen receptorIC 50 (nM)2.1N/AN/ADetails